Rational treatment of respiratory disease, especially acute respiratory failure and CO2 retention in chronic diseases, is based on the understanding of CO2 control of breathing. The medullary chemoreceptors play a crucial role in regulating breathing but the mechanisms governing their activity are not established. The role of catalysis of CO2 hydration in producing hydrogen ions and of anion (HCO3) exchange across cells (buffering this process) will be studied in anesthetized rats by administering blocking agents of these processes via CSF perfusion into the cisterna magna and measuring the ventilatory response to CO2. The relation between hydrogen ion activity in medullary chemoreceptor tissue and ventilation will be studied in anesthetized rats and cats by measuring tissue pH with a pH microelectrode inserted in the tissue and phrenic nerve activity during transient changes of arterial PCO2 and PO2. By measuring local tissue perfusion with a servo controlled temperature probe, with simultaneous measure of tissue pH, the response of blood flow in the chemoreceptor tissue to changes of PO2 and PCO2 and its relation to tissue hydrogen ion activity will be studied. The possibility of trans-arteriolar CO2 exchange will be tested by measuring tissue pH while changing arterial and CSF superfusate PCO2 in the same and in opposing directions. Theoretical description of CO2 transport in chemoreceptor tissue will focus on anion exchange, buffering and arteriolar exchange. These studies should provide evidence to reject or accept hypotheses of chemoreceptor mechanisms which are of cardinal importance.